The proposed studies concern the structure and function of human hemoglobin variants and the pathogenesis of the diseases associated with these variants. Eight examples of unstable hemoglobins are presently available for study. Clinical evaluation of the affected patients will include examination of the effect of splenectomy or of drugs on the rate of hemolysis, and will attempt to correlate symptoms with the functional properties of the hemoglobin and the degree of anemia. The molecular basis of hemoglobin instability will be explored and will include studies of hemichrome formation, thiol oxidation, subunit dissociation and heme-globin binding. The effect of Heinz body formation on red cell function will be studied. Study of two examples of unusual interactions between alpha variants and the beta chains of Hb S may elucidate further the molecular basis of hemoglobin instability and of sickling. The structure-function relationships of two hemoglobins with high oxygen affinity and two examples of Hb M will be examined. The possible relationship between the synthesis of fetal hemoglobin and other features of fetal erythropoiesis will be investigated. Studies of Hb F synthesis in cultures of red cell precursors and studies of NMR spectra of CO13 hemoglobin will be undertaken.